We developed the in vivo microdialysis technique to monitor prefrontal cortical-striatal interaction and neurochemical dynamics associated with cognitive behavior in the non-human primate. We have demonstrated pharmacological manipulation in the prefrontal cortex may result in significant changes in striatal dopamine (DA) levels. Augmentation of prefrontal DA levels by infusion of amphetamine or cocaine resulted in dramatic decreases in DA in the caudate nucleus. In contrast, reduction, of prefrontal cortical function by infusion of TTX, or of cortical dopamine function using flupentixol, a D1/D2 antagonist, resulted in significant increases in caudate DA levels. These data are the first to demonstrate, in both directions, the regulation of subcortical DA systems via cortical pharmacological manipulation in the primate. Caudate DA release can also be affected by limbic system damage within the temporal lobe. In an attempt to study how maldevelopment of temporal lobe limbic structures effects cortico-striatal dopamine function we studied the effects neonatal limbic lesions have on dopamine release in the caudate nucleus. While basal levels appeared to be unchanged dopamine overflow with K+ challenge was reduced nearly 50% compared with normal monkeys. Thus we have evidence that neonatal limbic lesions result in changes in dopamine release in the striatum in the primate. Recently, we have extended our studies to monitor some of the purported amino acid neurotransmitters, such as glutamate, and GABA. Extracellular GABA glutamate overflow were measured in the caudate nucleus and the prefrontal cortex and were characterized for voltage sensitivity and calcium-dependency. The results suggest that GABA and glutamate levels recovered from the rhesus monkey brain derive in significant part (>50%) from neuronal pools and are release dependent. We have applied the in vivo dialysis technique to the awake behaving monkey. Like the sedate monkey, DA was not reliably measurable in the area of the principalis sulcus in prefrontal cortex (PFC). Acetylcholine (ACh), however, was easily found in both areas. ACh was detectable and stable for many hours, was from neuronally derived pools, and was responsive to pharmacological manipulation. In both the hippocampus and PFC performance on a simple operant conditioning task, the recognition memory task, delayed nonmatching to sample, and the working memory task, delayed response with short delays, increased ACh levels (20 to 30%) significantly above baseline levels. In contrast, performance on a control motor task increased ACh only slightly (10%). Curiously the increase in ACh associated with the performance on the behavioral tasks peaked and remained high even after performance on the tasks end. These sustained levels of ACh after task completion were abolished with infusion of the sodium channel blocker, TTX, suggesting that the prolonged elevation was associated with neuronal release. Most recently, we have been able to demonstrate a double dissociation related to performance on the cognitive tasks DNMS and DR. While performance on both tasks raised ACh levels significantly above basal levels in both the hippocampus and PFC the levels varied within an area by cognitive difficulty of one of the tasks. This is the first demonstration of dynamic neurochemical events within a limited neural region that can be associated with specific performance on a cognitive task.